Innate signaling pathways can regulate influenza virus replication, and there are viral countermeasures, but there remain critical gaps in our knowledge about how these responses impact viral disease pathogenesis. The overarching goal of this highly integrated program is to systematically address these questions using a systems-based approach to reveal new therapeutic approaches. The goal of the Genomics Core is to provide a central resource that will facilitate high throughput sequencing of the transcriptome (mRNA-seq, GRO-Seq, and Nanostring gene expression analysis) and the epigenome (ChlP-Seq) in influenza virus infected cells. The core will also provide data analysis and integration to uncover the virus-host transcriptional response network. This information will be used by other program investigators in the Modeling Core to define host molecular networks and pathways that impact influenza virus infection and to define rare and disruptive gene polymorphisms that influence influenza virus disease pathogenesis (Project 3). Cellular networks, pathways, and genes that are implicated in the virus-host transcriptional response network will be targeted by RNAi-knockdown to determine how perturbations in the system impact the transcriptional response network to infection by wild-type and specific mutant influenza A viruses. These studies are critical for the overall goal ofthe program aimed at uncovering the global effects of influenza virus on cellular functions and on the system of key antiviral responses and virus countermeasures.